7-chloro-4-(1-ethyl-4-piperidylamino)-quinoline



UNITED STATES PATENT OFFICE 7 -CHLORO-4- (l-ETHYL- l-PIPERIDYL- AMINO) -QUINOLINE Billy Gene Parham, Urbana, Ill., assignor to the United States of America as represented by the Secretary of War No Drawing. Application April 8, 1946, Serial No. 660,410

1 Claim. (Cl. 260-288) 1 The present invention relates to a novel class of stituted quinoline, acridine or substituted acricompounds characterized by superior antimalaridine nucleus. a1 properties, and to methods of preparing the A more specific object is the provision of a, nov- Same el class of 4-aminoquinoline.compounds havin Within the past several years, interest in the 5 suppressive antimalarial properties approximatesynthesis of antimalarial drugs has been greatly 1y equivalent to those of SN-7618 and other prestimulated by the recently reported therapeutic viously known drugs, but characterized by a sigproperties of certain members of the acridine, the nificantly lower toxicity to the host or patient.

4 aminoquinoline and the 8 aminoquinoline Another object is to develop a suppressive anticlasses; notably 6-chloro-2-methoxy-9-(B-dieth- 1o malarial whose toxicity to the host is not only of ylaminopentyl-2-amino) acridine (I) or quina lower order of magnitude than that of SN-7618, acrine; 7-chloro 4 5 diethylaminopentyl-2- but of a qualitatively'difierent character. amino) quinoline (II) or SN-7618; and 8-(5'- Still another object is to provide suitable methisopropylaminopentylamino)-6-methoxy quinoods for the preparation of such drugs, starting line (111) or SN13276. with readily available raw materials, and con- Cm verting these to the desired drug by processes that may be carried out in readily available equipment, with high yields. A Other objects and advantages of the invention will be apparent as the description progresses.

Cl It has been discovered, in accordance with the N/ present invention, that the foregoing objects may u be attained by the synthesis of certain com- I g gf pounds having the characteristic side chain shown in IV.

In the 4-aminoquinoline series, the compounds in accordance with the present invention may be illustrated by those having the typical struc- C1 ture V N alkylcne II (SN-7618") NH-C N-alkyl CHgO- elkylene x N N NH-(CHDr-NH-CEHCHa):

III (SN-13276) The outstanding therapeutic properties of quinacrine, SN-7618 and SN-132'76 relative to quinine in the treatment of certain types of malaria has led to an intensive reexamination of other syn thetic compounds in the hope that even more ef- 1 ethy1-4-piperidy1amin0) quinoline fective drugs might be developed- (VI), which will hereinafter be designated SN- Broadly stated, the object of the present mven- 13425.

tion is to provide a new and improved class of CH CH synthetic antimalarial drugs having a novel type of side chain and characterized by the general -C N-mm structureIV wherein X represents a nuclear substituent such as halogen, the alkylene groups in V preferably being polymethylene groups. The preferred embodiment of the present invention, insofar as the 4-aminoquinoline series is concerned, consists of 0 Hz- C 1 alkylene Nucleus -NH--C N alkyl 0 alkylene N IV v1 (SN-13425) the nucleus in IV being either a quinoline, sub- For purposes of convenience and simplicity, the

preparation of the class of compounds IV in ac-- cordance with the present invention will hereinafter be illustrated by reference to the synthesis of a preferred embodiment, namely SN-13425. This compound may readily be p epa ed n high yields by the condensation of 4,7-dichlroquino sents a type of compound of which very few examples have heretofore been known. It is therefore desirable to explain in some detailseveral alternative methods of preparing the necessary intermediate (VIII) for the synthesis of the drugs of type V.

One method used for the preparation of the intermediate (VIII) takes advantage of the availability of 1-alkyl-4-piperidones (X) which may be prepared by the method employed by Bolyard and McElvain. [See J. Am. Chem. Soc. 51, 922

A more convenient method for the preparation of the intermediate IX in the above equations was found to be the addition of alkylamines to ethyl acrylate according to the scheme:

When this method was used example, a 91-94% ethyl)ethylamine (IX, R=ethyl) was obtained. The ring closure of this compound, and the decarboxylation of the cyclized product, carried out essentially according to the methods of Bolyard and McElvain [J. Am. Chem. Soc. 51, 922 1929)] gave 82-87 yields of 1-ethy1-4-piperidone hydrochloride, based on the bis-(fi-carbethoxyethyl)- ethylamine (IX) used. Since the low molecular weight piperidones of the general type X are known to be unstable, no attempt was made to isolate 1-ethyl-4-piperidone. Instead, the hydrochloride X salt was converted to the free base, the latter taken up in a solvent and converted in high yields by suitable means such as reductive amination to 1-ethyl-4-aminopiperidine (VIII).

(VIII) was then condensed with an equimolar proportion of 4,7- the desired 7-ch10rowith ethylamine, for

yield of bis-(,S-carbethoxy-- 4 4-(1-ethyl-4-piperidylamino)quinoline excellent yields.

In order more clearly to disclose the nature of the present invention, an example of the preferred method of preparing SN-13425 ['l-chloro- 4 (1 ethyl 4 piperidylamino) quinoline] will hereinafter be described in considerable detail. It should be understood however that this is done solely for purposes of illustration, and not with a view to delineating the scope of the invention or limiting the ambit of the appended claim.

Example described in detail below may follows:

(VI) in The procedure be represented as clncmmmtt No C H NH1-l-2CHz=-CHCO Et ollnN CIIQCIIQO( 1Et orncncomt (when,

no! Nil; mum c,lI,N\ o :0 IT? i 1 onion: HCl omonz 1 or omou can: CHNH; a omen. N

CH2 CH2 NHO N-cnn In the following description, temperatures are given in degrees centigrade.

Bis-(p-carbethoxyethyl) ethylamine-In a 2-1. round-bottomed flask, fitted with a rubber sto per carrying a soda-lime drying tube and a glass tube reaching almost to the bottom, was placed 325 g. (420 ml.) of commercial absolute ethanol. The whole was then tarred, placed in an ice bath and the inlet tube connected to a source of dry ethylamine.

flask was placed 240 g. of sodium hydroxide pellets. Forty grams of aqueous ethylamine was added and after the reaction had subsided an additional 160 g. of aqueous amine was introduced. The contents of the flask were shaken and warmed in such a manner as to effect a continuous stream of ethylamine. When the addition was completed, the flask and contents were removed and weighed. The increase in weight was 135 g. (3.0 moles).

The flask was immersed in an ice-salt bath and 640 g. (6.4 moles) of freshly distilled ethyl acrylate in 400 g. of absolute ethanol was added at such a rate that the temperature of the reaction mixture did not rise above 20. After such addition the flask was stoppered and allowed to stand for eight days.

The alcohol was removed by distillation under water-pump pressure and the residue transferred to an 8-in. beryl saddle still. After a small forerun (6 g.), 694 g. (94.4 of theoretical) of material was collected boiling at -111 (1.1 mm), n 1.4404 1.4395. A small sample was redistilled and submitted for analysis.

v 400 cc. of ice water.

Anal. Calcd. for C12H23O4N2 N, 5.71. Found: N. 5.53.

1ethyl-3-carbethory-4-plperidone hydrochloride.-To a 2-l.

CHgCHaCOzEt a C H N CHaCHaCOzEt CHICK! CHzCH amine (a total of 387 g., 1.58 moles) was thenadded at such a rate as to maintain gentle reflux (45-50 minutes). When the addition was complete, the mixture was stirred and heated under reflux for an additional hour. At this point, all of thesolid was usually in solution. The oil bath was removed and the reaction mixture allowed to cool for about five minutes, then poured into a 2-1. separatory funnel containing 200 g. of ice and The contents of the separatory funnel were shaken vigorously and the layers allowed to separate. An additional amount of water (250-300 cc.) was used to wash the xylene layer and to dissolve any salt which may have separated during the first washing. The aqueous layer was filtered and the salt washed with ether. The filtrate was then extracted with two 150-m1. portions of ether. The ether and xylene extracts containedno appreciable amount of either starting material or product, and were discarded.

The aqueous solution combined with the salt from the filtration was cooled below and while keeping the temperature at this point, the solution was made acid to Congo red with concentrated hydrochloric acid (260-275 cc.). The acidic solution was neutralized with solid technical potassium carbonate, cooled below 0 and placed in a 4-1. separatory funnel. Approximately 800 g. of potassium carbonate was added in two portions, with shaking. An orange layer of amine separated and was drawn off. The aqueous layer was cooled to 0, an additional 400 g. of potassium carbonate was added and the mixture extracted with a total of 1 l. of ether. The organic layer and ether extracts were combined and shaken with two 50-ml. portions of a saturated solution of sodium chloride.

l-ethyZ-ei-piperidone hydrochloride.The ether solution of 1ethyl-3-carbethoxyl-piperidone was extracted with a total of 430 m1. of hydrochloric acid (2'70 ml. of concentrated hydrochloric acid in 160 ml. of water). One hundred and fourteen milliliters of concentrated hydrochloric acid was then added to this solution (this theoretically gives a solution of 1-ethyl-3-carbethoxy- -piperidone hydrochloride in 20% hydrochloric acid), the dissolved ether was removed by heating, and the whole heated under reflux until a drop of the solution failed to give a red color when added to a 1% solution of ferric chloride (approximately four hours). The aqueous solutions of 1-ethyl-4-piperidone hydrochloride (light orange in color) was evaporated to dryness on a steam bath at water-pump pressure. The weight of light orange solid is 211-223 g. (82-87% base; on the his (fi-carbethoxyethybethylamine use 1-ethul-4-aminopiperidine.-Sixty-flve grams (0.4 mole) or the l-ethyl-i-piperldone hydrochloride prepared as directed above was dissolved in 'ml. of water in a 200-ml. Erlenmeyer flask and the resulting solution cooled to 2 and placed in a 500-ml. separatory funnel. The flask was washed with 20 ml. of water, which was also added to the separatory funnel. Seventy-five milliliters of cold ether was added and then 100 8. of technical potassium carbonate in portions with shaking. The ether layer was separated and the remaining pasty material extracted with three -ml. portions of ether. The ether extracts were combined and filtered rapidly through a double thickness of fluted filter paper. The filtered solution was dried for one to two hours over 15 g. of anhydrous magnesium sulfate and then filtered two times through a single thickness of filtered paper. Dry ether was used liberally in washing filter papers, etc. The ether was removed under reduced pressure keeping the temperature of the residue below 25. Approximately 50 ml. of a light orange oil remained. The oil was placed in a 270-ml. high-pressure bomb together with 40 ml. of absolute ethanol, 1 teaspoon of Raney nickel catalyst and 55 ml. of

liquid ammonia. An initial pressure of 2900 lbs. of hydrogen was introduced; the bomb was heated to 150, and shaken at this temperature for forty-five minutes. The bomb was cooled to room temperature and opened. The Raney nickel was filtered and the bomb washed well with dry ether. The organic solvents were removed under reduced pressure (water pump) and the residue distilled through a 6-in. column packed with glass helices. A small forerun was collected and then lethyl-4-aminopiperidine collected at 73 (16 mm); 29.3 g. (57% of theory); n 1.4725. A liquid residue (mainly l-ethyl-4-hydroxypiperidine) weighing 11.4 g. remained in the distilling flask.

A portion of the 1ethy1-4-aminopiperidine was redistilled and submitted for analysis.

Anal. calcd. for C'zH16N22 C, 65.57; H, 12.58; N, 21.85. Found: C, 65.14; H, 12.65; N, 22.15.

The amine hydrates rapidly when exposed to the atmosphere. The sulfonamlde of the amine was prepared by the usual Hinsberg method and was amphoteric as would be expected. It was not treated further. The picrate of this amine was formed in the usual manner. It was recrystallized from glacial acetic acid, M. P. 254-255 (dec.).

Anal. Calcd. for C19H22N8014: C, 38.91; H, 3.78. Found: C, 39.07; H, 3.95.

7-chloro-4-(1-ethyl 4 piperz'dylamine) quincline.In a 500-ml. three-necked, ground joint flask equipped with a. reflux condenser protected from moisture by a calcium chloride tube and a mechanical stirrer was added 38.2 g. (0.298 mole) of 1-ethyll-aminopiperidine, 57.4 g. 0.29 mole) of 4,7-dichloroquinoline and 30 g. of phenol. This mixture was heated with stirring at 150-160 for ten hours and at 160-168 for two and onehalf hours. While hot, the viscous material was 'poured into 160 cc. of a cold solution of 40 cc. of concentrated hydrochloric acid and 210 cc. of water. The remaining cc. of hydrochloric acid solution was used to dissolve the material which did not pour out of the reaction flask. About cc. of water was used for washing purposes. The

' a finely divided tan solid. The solid was filtered,

aqueous solution filtered, cooled to approximately The modifications in these two general methods 10 and extracted with three 150-cc. portions of required to produce the intermediates used in the ether. The light oran e aqu o s t n w preparation of the herein described drugs will be placed in a 2-l. beaker immersed in an ice bath di apparent to those skilled in the art. and while stirring made alkaline with cold 20% 5 However because f h availability of potassium g t term] eparated Dipcridones, the preferred method for the syn- An Orangel'own y ma 5 thesis of the corresponding 4-amino-piperidines which upon stirring for a short time formed .to appears to be the reductive amination of these washed well with water and dried for two hours l 5233 1 descubed m damn in the foregomg e dried solid was added to 2500 m1. a Qther modifications of the preferred of hot thiophene-free benzene which was then 680111.16 Wm be readlly apparent to t h m heated under reflux until solution was eifected. It will also be apparent a baslcprmclples Approximately 400 ml. of the benzene was dismaybe used for the p eparation f a wide variety tilled to remove water and then '7 g. of Norite and of compounds of the P IV lncluglngr for 400 ml. of benzene were added and the mixture fi P F pamaqume analogue XIII, the heated under reflux for five minutes. The soluqumacrme analogue XIV, and a host f Similar tion was filtered through a fluted filter and the compoundslatter washed with approximately 300 ml. of hot benzene. The filtrate was allowed to cool to room ("motemperature and then cooled in an ice bath. Fine white crystals separated, which were filtered and washed first with cold benzene and then with cold ether. The solid was dried in an oven at 80 for g- I orig-cu: two hours. Sixty-seven grams (80% of theory) Nnmufl cm of white crystals, M. P. 195-197 (with decomp.) was obtained. A sample was recrystallized from UHF-0H1 benzene and submitted for analysis. XIII Anal. Calcd. for CisHzoNaClc C, 66.31; H, 6.96; 30 N, 14.50. Found: C, 66.29; H 7.12; N, 14.26.

The foregoing procedure represents a method NIL-C11 N o,m of preparing the preferred drug, starting with CHPCH: readily available raw materials (ethylamine, ethyl acrylate, etc.) and proceeding by steps, all of which give high yields. Alternative methods may however be used if desired. Thus, for example, the 1-alkyli-aminopiperidine intermediates may be prepared by suitable modifications XIV of the procedures of Cerkovnikov and Prelog [Ber. 74B, 1648, 1658 (1941) Helv. Chim. Acta, 26, 1132 All these and similar variations, modifications or (1943)] who developed the following two methods extensions of the basic principles of the present for the synthesis of substituted 4aminopiperiinvention are to be understood to be included dines: within the scope of the appended claim.

Br-CHrCH; Hllr ll ICH2 C112 60 I claim:

0 D ()3 Nam 7-ehloro-4-(1-ethy1 4 piperidylamino) quln- I H I oline.

A A BILLY GENE PARHAM, H I L a J REFERENCES CITED N N N \N/ The following references are of record in the t it r'r 1'; file of this patent:

XII UNITED STATES PATENTS l Number Name Date The first method was applied by these authors mainly to the synthesis of dimethy1amino 1,903,196 Schulemann et al. Mar. 28, 1933 piperidines; however, l-phenyl-4-aminopiperi- 2233970 Andel sag et a] 1941 dine was also prepared by them in 45% yield 'by FOREIGN PATENTS the condensation of XI (R=H) with anlilline. A Number Country Date fif f of 5 g g i 6 134,218 Switzerland Sept. 16, 1929 3.121] 018 115111,, 19 SECOU me O OWeVeI', e Switzerland Jan. J

yields were not high-mainly because of the tendency of XII to lose hydrogen bromide to OTHER REFERENCES yi ld t t ahydr py i ine iva l-ph nyl- McElvain: Jour. Amer. Chem. Soc., vol. 48, 4-amino-piperidine was made in 14% yield by the pages 2179-2182 (1926)..

condensation of XII (kCsHs) with alcoholic Ru'bstov: Jour. Gen. Chem. (U. S. S. R.),vol. 9, ammonia. pages 1517-1524 (1939). 

